New Concept and New Way of Treatment of Cancer

By Xu Ze Xu Jie Bin Wu

This book is the scientific summary of the authors treatment experience on oncology surgery during his 50 years of oncology surgical practice and of the author's research achievement during his 20 years of animal cancer experimentation and clinical research. The book is divided into 38 chapters in which the author demonstrates innovative concepts of cancer therapy including a new cognition of cancer etiology and pathogenesis, new concepts and methods of cancer therapy and anti-cancer metastasis and recurrence. The author also demonstrates experimental information and analysis of clinically testified results and new ways of conquering the cancers from many aspects. The cancer existing in the human body has three forms: the two points and a line, and eight steps and three stages of carcinoma metastasis, the third field of anti-carcinoma-metastasis and recurrence treatment, three Steps of therapy of carcinoma metastasis, etc. It includes both the review and recall of traditional surgical and chemotherapy and radioactive therapy and the summary and analysis of the experimental information and clinical testifying results for XZ-C immunologic regulation and control anti-carcinoma traditional Chineses medicine which the author purified from the Chinese herbs. In addition, in this book the author added the scientific methods of the cancer therapy and the strategies and suggests for the overcoming the cancer development. Some part contents of this book have generated great attention in the international field of oncology. In this book the contents are creative and the ideas are new and the theories are related to the practices. There are extremely high scientific value and clinical application, which is a value reference for clinical oncologist, oncology specialists and oncology scientific researcher and the family and caregivers of the cancer patients.

• Language: English
• Publisher: AuthorHouse
• Release date: Apr 9, 2013
• ISBN: 9781481732710

Xu Ze Xu Jie Bin Wu

Brief Introduction to Author Xu Ze, male, born in Leping County of Jiangxi Province in Oct. 1933, gradated from Tongji Medical University in 1956, successively held the post of director of department of surgery of Affiliated Hospital of Hubei College of Traditional Chinese Medicine, professor, chief physician, tutor of postgraduate and doctoral student, President of Experimental Surgery Restitute Institute of Hubei College of Traditional Chinese Medicine, Director of Abdominal Tumor Surgery Research Room and Director of Anti Carcinomatous Metastasis and Reoccurrence Research Room. in addition, he held concurrent posts of Standing Director of China Medical Association Wuhan Branch, Vice President of Wuhan Micro-circulation Academy, Academic Member of International Liver Disease Research, Cooperation and Exchange Center, Member of International Surgeon Union, Standing Member of 1st, 2nd, 3rd and 4th Editorial Board of China Experimental Surgery Journal, Standing Member of 1st, 2dn and 3rd Editorial Board of Abdominal Surgery Journal. Enjoying Special Allowance of State Council. He has been engaged in surgery work for 49 years and accumulated rich experience in radical operation of lung cancer, esophageal carcinoma, liver cancer, carcinoma of gallbladder, adenocarcinoma of pancreas, gastric carcinoma and intestinal cancer as well as in clinical therapy with Chinese Traditional Medicine combined with Western Medicine of prevention of reoccurrence and metastasis after operation. He has been engaged in scientific research of surgery for 15 years and obtained many fruits, among which the task of Experimental Study and Clinical Application of Self-made Type Z-C1 Abdominal Cavity---Vein Flow Turning Unit in Therapy of Chronic Ascites of Hepatic Cirrhosis issued by Science Commission of Hubei Province was awarded Second Prize of Scientific Fruit by People’s Government of Hubei Province and was popularized and applied in 38 hospitals in 12 provinces all over the country in 1982. The task “Experimental Study on Physiological Mechanism and Pathogenesis of Schistosome with Method of Experimental Surgery” , issued by National Natural Fund Commission was awarded Second Prize of Scientific Fruit by People’s Government of Hubei Province in 1986. He began to study the tumor experience, established the tumor animal model and metastasis and reoccurrence animal model and probed into the mechanism and rules of carcinomatous metastasis and reoccurrence to find out the method to inhibit the metastasis. 48 kinds of Chinese traditional herbs that could counteract the intrusion, metastasis and reoccurrence were found and selected from a large number of natural herbs. Based on this, he invented and developed China Xu Ze (Z-C) Medicine Treating Malignancy, which had remarkable curative effects through over 10 years’ clinical validation of many cases. He has been engaged in teaching for 40 years and has cultivated many young doctors, 10 masters and 2 doctors. He has released 126 papers, published New Understanding and New Mode of Therapy of Cancer as the editor in charge; participate in writing 8 medical exclusive books including Therapeutics of Liver Disease, Surgery of Liver, Gallbladder and Pancreas and Surgical Operation of Abdomen.

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CHAPTER 1

The Concept of Traditional Cancer Therapeutics Should Renew Thought and Change Conception

I. Cancer therapeutics should be established based on the understanding of the concept of cancer

After the Second World War, oncology has developed greatly at home and abroad for half a century. The traditional three therapies and operative tumor therapy have a history of over one hundred years, while radiotherapy and chemotherapy have a history of 80 years and nearly 60 years respectively. In 1980s, biotherapy and immunotherapy arose. Quite great progress has been made in the curative effect of tumor and relatively better curative effect has been achieved for many tumors, however, the curative effect of an abundance of tumors are still in extremely poor state.

In 1985, the author made follow-up survey to over 3000 patients who had experienced general surgical and chest cancer operations performed by the author, and found that most the patients experienced recurrence and metastasis within 2 to 3 years after the operation or even within several months for some patients, from which I deeply realized that the operation was successful and standard, but the long-term effective was unsatisfactory or even unsuccessful.

Since 1970s, in view of the extremely high recurrence and metastasis rate after operation, to prevent the recurrence and metastasis after operation, a series of assistant chemotherapy has been adopted after operation or even before operation (such as mastocarcinoma), but the results have been not satisfactory. Recurrence and metastasis still appear in or after the course of assistant chemotherapy after operation or appear along with chemotherapy; I have observed from a great many of patients in our tumor special clinic that assistant chemotherapy after operation fails to prevent recurrence and metastasis and intensive recurrence and metastasis causes the failure of immunologic function to some cases. The clinicians should seriously, calmly, objectively and practically consider, review, analyze and turn over to think the above facts. Many basic concepts and theories are still not clear and the curative effect is not high, therefore, we must make clinical fundamental research in depth and it will be difficult to improve the clinical curative effect in case of no breakthrough in fundamental clinical research.

(I) Review of the history of traditional therapeutic method

The establishment of scientific basis of modern medicine for cancer only has a history of over one hundred year. The traditional cancer therapeutics, i.e. three therapies, have taken shape gradually in the past one hundred years and is established on the basis of traditional mode concept of cancer. We will briefly review the formation of traditional mode concept of cancer and cancer therapeutics of modern medicine and their contributions to anti-cancer achievements of human beings.

The classical tumor mode concept was established based on the understanding of integrated level of cytology, pathology, cell biology, microbiology and anatomy and cellular level in the end of 19th century and the first half 20th century. In those days, the subjects concerning cellular level really accelerated the great development in medical science. They held that the tumor cells were converted from normal cells which would have abnormal formation, metabolism and functions after converted to tumor cells. Tumor cells grew vigorously and continuously, lacked coordination with the whole organism of host, and disabled it from maturation to different extent. They held that tumor originated from individual cell, that is to say, tumor was originated from clone, cancer cells were able to regenerate autonomously and were divided and reproduced continuously, one to two and two to four, therefore, cancer cells were the arch criminal and the root of canceration, and they must be killed. All of the cancer cells must be killed for therapy. The scientists at the beginning of 20th Century sought the method to kill cancer cells.

1. In 18th Century, distinguished doctors held that cancer was local disease and could be cured by surgical operation. In 1881, Billroth firstly performed the surgical radical operation on tumor, i.e. partial gastrectomy. In 1888, Langen Buch successfully resected pedicel bearing tumor on the left lobe of liver. In 180, Halsted performed radical mastectomy, illuminated the principle of en bloc resection for the first time, i.e. primary tumor was resected together with local lymphatic vessel and lymph nodes, laying the foundation for the most modern tumor surgical operations. The technology of surgical tumor resection operation was developed along with the development of surgical medicines; after the middle period of 20th Century, the range of tumor surgical operation became larger due to the progress in the technology of surgical operation, a series of super radical operations, such as expanded radical mastectomy. It was proved by the practice over years that the expanded surgical removal range could not improve the tumor-free survival time and total survival time for most cancerous protuberances, such as lung cancer, liver cancer and cancer of pancreas.

2. In December, 1898, Curie found radium, a new trace element that she had been seeking for a long time, and obtained Nobel Prize in 1911, and radium had been extensively researched and applied in medical science since then. However, radium had a certain lethal action. In 1930s, the doctors observed that when the workers in clock and watch factories painted the radium pigment on the figures on dial plate, they had the habit of licking the stylus, and many of them caught bone cancer. Furthermore, Curie died of leukemia in July, 1934; unquestionably, this was the direct result of radiation of radium. It was proved by facts that radium was quite effective to massive tumor, any tumor would shrink rapidly after injection with syringe needle painted with radium on the tip, and the radium therapy was the main method for cancer treatment for decades of years. 800-1000kV X-ray machine was developed in 1932 and cyclotron and induction accelerator were developed subsequently. Radicisotope was applied to tumor treatment step by step. At present, although the radiotherapy has certain effect on the treatment of various tumors, the effect is still not ideal in general, and the main reasons of unsuccessful treatment include recurrence and metastasis.

3. After the Second World War (1946), it is found that the cell toxicant (Nitrogen mustard) and its derivation in the chemical warfare have obvious inhibitory action on tumor, however, due to its poor selectivity, it is called cytotoxic drug, it can kill cancer cells and kill the normal cells of host at the same time, so the toxic side effect is relatively large. The existing therapy design is still established on the basis of logarithm value—cells—killing, which is derived from growing mode of L1210 leukemia cell strain. It is embarrassing that the killing mode of one logarithm only indicates the resistance of host rather than therapy. As to the vital cancer cells, after each therapy, there are still some left and they can’t be thoroughly killed.

The above-mentioned three therapies of traditional therapeutic method have made great accepted contributions to anti-cancer achievements of human beings. However, up to the beginning of 21st Century, cancer is still very rampant, the incidence rate of cancer grows continuously, the death rate is still quite high, and the recurrence and metastasis still cannot be prevented, even though many patients receive normal and systematic radiotherapy and chemotherapy after operation. Why the traditional therapy cannot obviously reduce the death rate? Whether it is presented that the traditional therapy does not conform to the actual conditions of the biological characteristics of the carcinomatosis? What is the matter with the traditional concept and the traditional therapy? What is the defect? How to correct the defect in concept or understanding so as to make it more perfect and more coincidental with the actual conditions of molecular biological characteristics of the carcinomatosis?

In view that the concept of cancer therapeutics is established based on the understanding of the cancer concept, it is necessary to research the new progress in cancer concept so as to research the concept of cancer therapeutics.

As to the understanding of the concept of carcinomatosis, Harvey Schipper had incisively elaborated it.

(II) Traditional mode of cancer

Fundamental principles of traditional mode: the contents of the traditional mode of cancer can be divided into five fundamental principles.

1. Cancer is of asexual reproduction (clone): the formation of carcinoma stems from the canceration in the single cell, so no matter how the canceration is induced, the tumor is endowed with all characteristics of tumor by this cell.

2. Autonomy of malignant tumor: the cancer cells are continually divided and proliferated and they do not obey the regulation and control, they are autonomous in behavior, the tumor cells grow as per the index, so it is thought that the growth rate is stable.

3. Irreversibility of canceration process: the canceration process has shown its irreversibility in a certain stage before clinic. The cellular aberration not only advances continually but also accumulates, resulting in failure of treatment, as is the natural development of canceration process.

4. Relation between tumor and host: the reaction of the host to the tumor is objective, however, its impacts on the natural disease process of the tumor is not inevitable.

5. It is required by the heal to kill the last cancer cell: if the canceration process is irreversible, autonomous and lethal, the only way to healing is to kill off all cancer cells. In case of remained cancer cells, they will be proliferated again; in case of remained tumor or unapparent tumor, it is regarded that the treatment fails and the patient will meet with death.

(III) Concept of traditional cancer therapeutics

It is held by the traditional concept that cancinoma is the continual division and proliferation of cancer cells, so the treatment must target killing the cancer cells, so these three goals of traditional cancer therapeutics are determined based on the concept of traditional mode of killing off the cancer cells.

The principle of current cancer therapeutics is based on the following precondition: in order to achieve the goal of heal, it is necessary to kill or eliminate the last cancer cells. As a result, people adopt the expanded operation and strengthen chemotherapy and radical radiotherapy. However, the curative effects are not so satisfying. At the beginning of 1960s, the extent of surgical operation on tumor tended toward expansion and a series of super-radical operations had been developed. Subsequently, it has been proven by the practice for years that the expansion of extent of surgical removal of the cancer cells, such as breast cancer, lung cancer, liver cancer and pancreatic cancer, has not improved the cancer-free survival time and total survival time. In 1980s, the one receiving intensive chemotherapy and radical radiotherapy could not achieve the improvement of survival quality or elongation of survival time. Since the hematopiesis function and immunologic function of the bone marrow are seriously restricted, some complications endangering the life are coming out. Therefore, it is necessary to establish a new mode to probe into the cancer, strive for opening a new way and renew the concept from the clinical and experimental data.

The classic concept of tumor mode is derived from microbiology. Penicillin was discovered by Fleming in 1929 and streptomycin was discovered in 1944. The clinical application of antibiotics has played an important role in controlling or eliminating a few of contagious diseases and infectious diseases. Microbiology veritably protests at thorough elimination of the exotic disease disseminators. When the patient suffers from the seriously infectious disease, such as lobar pneumonia, acute tonsillitis and so on, it is necessary to kill the bacillus for treatment with antibiotics, if the curative effect is not so good, the antibiotics sensitive to pathogenesis will be selected, the dosage will be increased or the combined administration will be adopted to thoroughly eliminate the pathogenesis. However, infection is quite another thing from tumor, the latter stems from the host body. When treatment of cancer with radiotherapy and chemotherapy is not ideal, it is possible to increase the dosage as the anti-cancer cytotoxic drug differs from the antibiotics: 92643.jpg The anti-cancer cytotoxic drug kills the cancer cells as well as the normal cells, inhibits hematopiesis function and immunologic function of the bone marrow and has the side effects on the liver and the kidney, if the dosage is increased, the host cannot withstand it; 94430.jpg Generally, anti-cancer cytotoxic drug cannot be used for drugsensitive test or drug resistant test and it is only blindly administered by experience while the antibiotics can be used for drugsensitive test so as to select the sensitive antibiotics.

To sum up, the concept of traditional cancer therapeutics holds the tumor is based on the maniac division and proliferation of the cells, so the cancer cells are the arch criminal, as a result, the target of the treatment goal of the traditional cancer therapeutics is the cancer cell, namely killing-off of the cancer cells.

II. Heal shall be realized through regulation and control instead of killing

(I) Assumptive new mode of cancer therapeutics

The assumptive new mode of cancer therapeutics includes some new examples and its predominant idea holds that cancer is a kind of disease, the regulation and signal transmission among the cells are disrupted instead of loss and the carcinogenesis is a continuous entity with possibility of reversion.

The understanding of the cancer by the new mode is based on information transfer and regulation and control. It is convinced that the canceration is a process of evolvement step by step, however, it holds that they may be potentially reversed. The last step of healing the cancer is to mobile the reappearance of the regulation and control role of the host instead of eliminating the last cancer cells. This mode refers to the experience and phenomena of clinical lab and epidemiorlogy as well as the modern molecular biology and traditional concepts. Based on the viewpoint of new mode, the mechanism that the cancer is healed through regulation and control may be presented and other pending issues may be explained.

The cancer cells do not always differ from the normal cells greatly. It has been clearly convinced from the present and previous observation that autonomy of tumor is very limited. Through the clinical observation over one century and the analysis in the past 20 years, the biological findings have definitely convinced that the cancerization course can be reversed. We had treated the cancer through killing off the cancer cells to the utmost extent, but we had not made great achievements. When it looks as if the condition is controlled, new cancerization may take place again. It has been proven by the past experience and the progress of modern science that the cancer cells can coexist with the host and they do not always damage the host.

All of these facts tell us that it is time to reconsider the mode of cancer treatment, which needs adjusting out understanding of cancer. Maybe our understanding is established on the concept that it is necessary to kill off the canceration cells as they can not be reversed, restricting our ability of understanding and treating cancer in an all-round way. Based on the above-mentioned, a new mode of cancer treatment is gradually formed.

(II) Fundamental principle of new mode

1. Clone: cancer is an evolvement process instead of a morphological solid, formation of tumor individual stem from the single cell in the organism, however, the tumor cells have been making the accommodation to the local environment.

2. Most of the structure of the cancer cells is normal: its malignancy characteristics result from the change in few genes and (or) environment. Except the lost genes, all signals of the other cell genes will be remained and the abnormality of the genes is mainly caused by the abnormality of regulation and control of expression. At present, it is shown by the increased facts that each functional part of the canceration is related to the characteristic gene product, which is consistent with the clinical observation. It can be reasonably inferred that the tumor grows, infiltrates and transfers under the proper conditions and the evolvement at each step depends on the exiguous reaction of the gene product with characteristic code. Now a kind of metastasis inhibiting gene (nm23) and its product have been discovered, which further indicate that the canceration has the intrinsic reversibility.

3. Unbalance of regulation and control: the reaction of host determines the final results. It is shown by the above-mentioned that the canceration results from the unbalance of regulation and control instead of the adequate autonomy. It is indicated by the clinical and experimental experience that the tumor keeps a certain response relation with the host. When the tumor results from the unbalance of regulation and control instead of the autonomy of the tumor, some clinical phenomena can be easily understood. Clinically, it is known by us that the cancer cells can make adaptative response to the environment of the host at high level. The long-term application of immunosuppressant may induce the tumor, when the immunosuppressant is suspended, the tumor can be entirely released. Although the factors inducing the tumor have not been proven, the reaction of host determines the final results. The kidney transplantation tumor with metastasis to the lung will be entirely released after suspension of the antirejection therapy. It looks as if the pregnancy improves the relation between the tumor and the host. Now people have focused on killing the tumor, developed so many therapeutic methods and developed many anti-cancer cytotoxic drugs in the past half a century, however, they cannot prevent the attack and metastasis of tumor. Viewed from the data, the cytotoxic drugs as the assistant of radiotherapy after operation also cannot prevent the reoccurrence and metastasis of the cancer because most of them severely inhibit the immunity even the non-immunological part of the host reaction. When people increase the concentration and dosage of the chemotherapeutic drugs to make them more aggressive to the cancer cells (such as intensified radiotherapy), we right lead the mechanism of long-term survival or healing to the more dangerous way, even bring about the artificial or iatrogenic immunologic function breakdown.

4. Reversibility of cancer cells: reversibility and anti-metastasis of tumor

As above-mentioned, since the tumor arises from the normal tissues, then, whether are the cancer cells reversed to the normal cells? It was regarded as a mirage scores of years ago, however, the history of scientific advance has proven for times that the mirage can be realized. Just because of this, at present, the scientists are seriously studying this task so as to control the cancer cells artificially by all means to make it free of malignant growth, recover and change the cancer cells into normal cells.

If the canceration is gradually induced and is not lethal immediately, the canceration cells possibly have the reversibility. The cancer cells can be reversed to the normal cells by means of a series of approaches including the change of a batch of processes before reversion induces the canceration; blockade of the incomplete or false signal transmission role; control over ineffective enzyme and accepter or the way of inducing metabolism dromotropic action. However, the metabolism of most of the cells has the capacity of keeping balance, in addition, in order to heal the patient suffering from the tumor, it is not required that the canceration meet with the reversion in all directions, it is only necessary to regulate the key steps such as proliferation, infiltration and metastasis of cancer cells again or make the key steps reversed.

Viewed from molecular biology, the cancer results from the change in DNA structure. It is the unbalanced differentiation of the cells caused by the genetic information that introduces the normal nucleic acid to the cancer cells via the genetic engineering, inducing the tumor cells to differentiate to the normal cells. Shanghai Tumor Research Institute had extracted RNA from the normal hepatic cells, then incubated and cultivated it together with the liver cancer cells to correct the abnormal genetic activities of the liver cancer cells through the regulation and control reaction of normal liver RNA so as to make it reversed to the normal cells. The scientists now are looking for the bioactive substances related to the genetic information, for example, the normal mRNA can induce the cancer cells to reverse to the normal cells.

Some drug has the probability of inducing the cancer cells to differentiate to the normal cells.

In recent years, a kind of cell fusion technology has been developed, which can make two kinds of different somatic cells fuse with each other. If the fibrocytes of the mouse fuse with the cancer cells of the mouse, the hybrid cell obtained become a kind of intermediate cell, with the intermediate texture and biological characteristics.

The work to induce the cells to differentiate to the normal cells to reverse the tumor cells is just remaining in the early stage, no matter the rule of regulating and controlling the cell differentiation with nucleic acid or the rule of regulating and controlling the cell differentiation with drugs, is not made clear and it needs further study. Therefore, the burden is heavy and the road is long!

Some scientists hold that it is possible to realize the reversion of the tumor in the early stage of the canceration while the tumor becomes an irreversible canceration in the late stage of the cancer, therefore, they put forward a suggestion: it is not necessary to induce the tumor to return to the normal state, but it is necessary to induce the tumor to differentiate to mature or make for apoptosis and death. It looks as if this is a more realistic assumption, in this way, it is likely to make the patients suffering from the advanced cancer enjoy the achievements of studying on tumor induction and reversion.

5. Killing tumor cells: the precondition of adopting the cytotoxic drugs to treat the tumor is the understanding that the it is not only possible but also necessary to kill the last cancer cell until it is proven by the clinic application and the lab that the tumor has been entirely eliminated, as is the prerequisite of healing the patient suffering from the tumor. However, according to our experience over 20 years, this argumentation is contradictory. Some clinical cases show that killing can shrink or subside the tumor, however, it cannot directly heal the tumor. Although the dosage of cytotoxic drug is increased and most of the cancer cells are subsided, the survival rate of the patient is not improved. Soon after, it will reoccur and the tumor will be enlarged.

All the obviously healed patients do not seem to adopt the mode of killing the cancer cells. For example, the treatment of tumor with platinum-based drug seems to be related to the induced cell differentiation. The action of interferon and interleukin to the sensitive cells is realized by the regulation and control mechanism. As to the levamisole as the adjuvant for carcinoma of large intestine, it is deemed that its effects are from the change in host reaction.

We had tried out best to kill the cancer cells to treat the cancer before, however, no great achievements had been made. Later, enlarged radical operation, intensified chemotherapy and radical radiotherapy were adopted. However, the results were not ideal and they could not improve the survival quality of the patient suffering from cancer and the survival time of the patient suffering from cancer after operation.

In the recent 50 years, the treatment of cancer by traditional Chinese medicine has made great achievements. A large number of data indicate that the cancer cells can coexist with the host and they may not always damage the host. In the recent 16 years, among 12000 patients suffering from metaphase and advanced cancer treated by Shuguang Tumor Research Institute and Wuchang Shuguang Tumor Special Clinic, some reoccurrence and metastasis patients, such as the patients with anastomotic stoma reoccurrence cancer and gastric carcinoma that cannot be ablated or treated through radiotherapy and chemotherapy, after taking Z-C medicine for a long time over 3-5 years, the conditions are controlled and stabilized, they can survive with tumor (coexist with the tumor) and take care of themselves, the survival quality is good and the survival quality is obviously prolonged.

Conclusions: this mode is not completely new, it is mainly the response to the new knowledge challenging the traditional concept and tries to conceptualize the canceration of the cell based on this. Now the most effective killing therapy we know at present is the most potential factor inducing the tumor and resulting in cell resistance. In the past scores of years, we have been catching a sight of epigamic circumstance that the treatment without cell toxicant can heal the tumor once in a while. Despite all this, the therapeutic direction that the people strive for is to kill the last cancer cell. If the therapeutic direction meets with new conversion, maybe our visual field will be broader. We should open a new road to reform and innovate the therapeutic concept.

It is deemed by us that undoubtedly we should kill the foreigners invading the body, however, as to the cancer cells, we shall make a differential treatment just because they are only the variant tissues in the normal body of the host, here we reaffirm that the cancer shall be treated through regulating the control over them by the mechanism instead of the necessary and impossible killing-off of all cancer cells.

Since we have a new cognition of the cancer concept, then, the concept of cancer therapeutics shall renew the thought, the understanding and the concepts and innovate the therapeutic theory and technology.

In view of the experience and lessons of the author over half a century, now we should research the urgent problems in the current cancer study, seek for the breakthrough for clinical research from the weak link of the modern medicine and find the breakthrough of prevention and control from the invasion, reoccurrence and metastasis, look for the anti-reoccurrence and anti-metastasis drugs from the chemical drugs and the natural herbs and deepen the new understanding of the cancer concept at the molecular level, genetic level, integrated treatment level and targeted treatment.

III. New progress of research on cancer and new trend of therapy

(I) New progress of fundamental research on cancer

Most research on tumor is conducted combining with clinic work. To overcome cancer, it is necessary to get a deep understanding of the nature of cancer, recognize cancer from the perspective of pathogenic factor, pathologic physiology, pathogenesis, pathology, heredity and immunity, and reveal the nature of carcinoma. The solider the fundamental theoretical research on carcinoma is, the richer are the specific measures of anti-cancer.

1. What is the origin of carcinoma? Scientists in ancient and modern times, in China and elsewhere, have explored the question for hundreds of years, but it remains an unrevealed mystery. How does a normal cell changes into a cancer cell? How can cancer cell itself evolves into tumor? Why cancer cell can pass down its character of excessive growth to the coming generations, and lead to human death?

To reveal the secret of excessive growth of tumor and passing it down to the coming generations, many scientists in the past have done much work, but most of it is rather rough restricted by historical conditions and what has been observed is often superficial. Until sixty years ago, i.e. 1950s, an unexpected experiment result was found that when a toxic diplococcus pneumoniae, killed at high temperature, was mixed with a nontoxic diplococcus pneumoniae and injected into the body of a mouse, the mouse would die of disease, and toxic diplococcus pneumoniae could be separated out of the dead mouse. This was a revealing experiment. How dead diplococcus pneumoniae recovered? How nontoxic diplococcus pneumoniae became toxic? It could not be explained at that time. Ten years later, someone cultivated the extract of toxic diplococcus pneumoniae together with nontoxic diplococcus pneumoniae, it turned out that nontoxic diplococcus pneumoniae became toxic. The extract was DNA. It was demonstrated by experiment for the first time that the basic substance of heredity was DNA. How DNA controlled heredity? It proved that the genetic code existing in DNA molecule controlled all hereditary characters.

How genetic code transfers genetic information? There are two approaches, one is DNA self-duplication, the other is NDA controls protein synthesis through RNA, i.e. DNA transfers genetic information to RNA and controls protein synthesis through delicate matching of three RNAs. DNA duplication and DNA’s controlling protein synthesis through RNA is a very close and rigorous process. Normal cells follow this rule strictly and maintain normal functions. However, some link of the complex process may mutate or go wrong disturbed by internal and external factors of the organism, triggering changes in DNA structure and function, some of which become malignant information and incur canceration. Previous theories of carinogenic factors are divergent and controversial. Currently, the studies on carinogenic factors begin to converge, whether chemical carinogenic factors such as benzene and nitrosamine, physical carinogenic factor such as radioactive rays, or biological carinogenic factor such as virus. They all acknowledge only by affecting DNA genetic information can cancer be incurred. DNA is damaged by these factors at first and incompletely rehabilitated, disturbing the sequence of nucleotide on helix chain, i.e. incur error of genetic code. As the wrong code is passed down, normal cells cannot retain their original genetic characters, changing the cells of the next generation into cancer cells and triggering crazily growing carcinoma.

Since mid-1970s, with the new progress of life science, establishment and development of DNA recombination, gene transfer and hydridoma technology, genetic engineering, protein engineering technology, it is possible to study the nature and characteristics of cancer cells by a combination of molecular level and cellular level, and find out anti-cancer approaches and reverse and differentiation or cancer gene treatments. Development of these special technologies accelerates revelation and recognition of malignant behavior of tumor cells, lays a foundation for controlling tumor occurrence, reduce the rate of suffering from cancer and death rate.

The basic biological character of tumor cell is manifested as disorderly regulation of cell proliferation and differentiation. In recent years, owing to the discovery of growth factor and growth inhibitory factor, people have got an understanding of regulation of cell proliferation and differentiation.

As is known to all, cell growth, death and differentiation are the most fundamental physical activities of the cell and basic issue of life science. Whether for growth factor, hormone or oncogene products, apoptosis, their effects of promoting cell proliferation and inducing cell death come down to affecting operation of the cell cycle, which is under the control of cell cyclin dependent kinase and its inhibitors. Cell continuous proliferation, apoptosis and reduction caused by abnormal regulation mechanism of cell cycle are the core of uncontrolled growth of the tumor cell. Hence, tumor can also be deemed as a cell cycle disease.

In mid-1980s, the research on tumor occurrence mechanism has made great advances. Most tumors are monoclonal, need to go through several steps to change from normal cells into malignant cells, which manifested as obviously different development stages. More importantly, the application of molecular biological technologies reveals that there is a close relationship between tumor occurrence and abnormal gene: 92645.jpg about 5% human tumors are inherited from the family; 94433.jpg the occurrence of all tumors is accompanied by somatic cell mutation, tumor development involves abnormal expression of multiple genes; 94797.jpg multiple carcinogenic factors such as virus, radioactive ray, chemical carcinogen, can all cause gene mutation; 94949.jpg the gene involved in tumor occurrence and evolution are often related with such basic life activities as cell proliferation, differentiation and apoptosis. Hence, it is recognized that tumor is a gene disease.

After 1976, the scientists discovered and recognized the nature of oncogene such as V-src, ras myc. Ten years later, they noticed the functions of tumor suppressor gene such as Rb, P53 and P16, opening up a new era of recognition of tumor in all aspects. Given the boom of research on gene therapy and apoptosis emerging at the end of 1980s and beginning of 1990s, the relationship between apoptosis or programmed cell death (PCD) and tumor drew more attention. It was believed multicellular organism maintains self-stability through cell proliferation and apoptosis, and the imbalance of them can cause tumor occurrence. It has been proved that inhibited apoptosis may be one of the tumor pathogenesis. However, it should be pointed out that proliferation, differentiation and apoptosis of normal cells are under strict control of gene. Therefore, uncontrolled cell proliferation, differentiation obstacle and apoptosis hindrance are just representation of tumor occurrence. To reveal tumor occurrence mechanism in essence, it is necessary to explore the change in gene structure or abnormal gene expression behind these representations on gene level.

2. The contact of human body with carcinogenic factors, even occurrence of cancer cells in human body, will not necessarily cause carcinoma.

As a matter of fact, not a few abnormal cells occur in healthy human body everyday, but they are not likely to grow and proliferate on a large scale and eliminated by immune system of the body. To ensure relative stability of its own genetic information, eliminate harmful mutation of DNA molecule, kill cancer cells in the body, human body has a whole set of immune defense system, which will give out alarm signals in case of occurrence of abnormal cells. In 1980s, the scientists separated out an alarm signal of malignant tumor, referred to as recognition factor, which was a kind of protein, gave out alarm, announced the occurrence of cancer cells in the body and summoned leukocyte responsible for cleaning to attack cancer cells. They also found that fewer recognition factors in the body of the cancer patient meant more serious tumor.

Carcinoma tends to occur to a few people whose immunologic function is damaged. Some people with congenital immunodeficiency tend to suffer from cancer. Behind the breast bone there is a glandular organ called thymus, which is an important immune organ of the body. Seniors’ immunologic function degenerates due to thymus atrophy, increasing the rate of carcinoma occurrence. In 1985 while the author was conducting the experimental study of modeling of animal inoculated with tumor cells, he made over 400 modeling experiments, which all failed, and later ablated the mice’s thymus first, leading to complete success in modeling. The conclusion of the experimental study confirmed there was a relationship between immunologic function organs and tumor occurrence.

Therefore, carcinogenic factor is an aspect of tumor occurrence, i.e. the external factor, while immune defense capacity of the organism is another aspect of tumor occurrence, i.e. the internal factor. The external factor effects through the internal factor, and the organism’s internal factor finally controls tumor occurrence. A seed cannot take root, geminate and grow without suitable soil. As what is soil to the seed, cancer cell cannot evolve into tumor before escaping from the monitoring of the body’s alarm system and breaking through the immune defense line of the organism. Far-sighted medical scientists and clinic scientists all have expectations of the field. We predict that future cancer treatment will derive from the immune defense system and adopt the approach of immunologic regulation, rather than just killing cancer cells by mere surgical operation and radioactive or chemical therapy.

According to our current recognition, the formation of most tumors in the body can be generalized as three procedures: first, carcinogenic factor (physical, chemical and biological) acts on the organism, disturbs cellular metabolism; second, disturb DNA genetic information within the nucleus, hereditary variation of the cell triggers canceration; third, cancer cells escape from immune alarm monitoring and defense system of the body, begin to split and proliferate, forming carcinoma.

The theoretical basis of therapeutics stems from the above theoretical basis. In view of the above new recognition, cancer should be treated through regulation rather than injury.

There have been two views of cancer occurrence and evolution:

One view is that cancer occurrence and evolution is an independent process basically unrestricted by any defense mechanism, treatment should focus on tumor itself while paying little attention to regulating effects of immune system of the organism. The other view is that cancer occurrence and evolution is a dependent process or controlled process regulated by multiple factors within the body, especially immune factors, which entails that treatment should pay equal attention to eliminating the pathogenic factors and reinforcing the vital qi. We hold that the process cannot be controlled effectively unless combine and apply the principles of reinforcing the vital qi and eliminating the pathogenic factors in a medical sense.

(II) New trend of therapy

The research on tumor biology and therapeutics must be consistent with the latter based on the theoretical basis of the former. Until now, tumor biology has developed to the level of molecular biology, cytokine and gene, while the theoretical basis of tumor therapeutics remains at the cytology level half a century ago, which is constant proliferation of cancer cells aimed at killing cancer cells. The traditional method is killing cancer cells, so using cell toxicant is not very effective, which is solved by increasing the dosage and adding several drugs for combination. Since 1980s, with the rapid development of molecular medicine, molecular immunology and cytokine study, new biological therapeutics emerges and tumor therapeutics advances.

It can be deemed that the research on anti-cancer medicine has entered a new stage, facing updated theories, technologies and ideas. The traditional idea and work method based on cell toxicant is under attack, research scope of anti-tumor drugs has not been limited to traditional cell toxicant drug, differentiation inducer and biological reaction moderator, immunologic regulatory Chinese medicines combining Chinese and western medicine are emerging.

1. Immunological therapy: as the clinic evidence related with immunity and immune index such as spontaneous extinction of individual tumor indicate that immunologic function of the organism is declining with the evolution of tumor, enlightening us to expect much of immunologic therapy of tumor. Many scholars and clinic doctors were once committed to pioneering this field with great interest, to make break-through progress in cancer treatment. However, after several booms and peaks, until the end of 1970s, although the research on cancer immunologic therapy achieved some results in animal experiment and in vitro experiment, the treatment effects in clinic experiment are not satisfactory enough.

Since the beginning of 1980s, the rapid development of cell biology, molecular biology and biological engineering technology has brought about new opportunities for cancer immunological therapy. The theory of biological response modifier (BRM) renews the recognition of traditional tumor immunological therapy and establishes the fourth tumor treatment formula beyond operation, radioactive therapy and chemical therapy, i.e. biological treatment of tumor. The establishment of BRM theory provides theoretical basis for biological treatment of cancer, and the development and utilization of biological engineering technology makes possible the clinic application of biological treatment of tumor. The use of cell engineering technology can produce large quantities of cell toxicant active cells such as macrophages, cell toxicant T lymphocyte, killer cell capable of naturally killing cells and lymphokine activation, as well as hybridoma cell excreting monoclone antibody. Genetic engineering technology can produce tens of cytokines for BRM such as interleukin, interferon, tumor necrosis factor, immunoglobulin factor and colony stimulating factor in large quantity.

The progress of the above biological technologies and deep understanding of cellular immunity provides opportunities for humans to develop immunological treatment of malignant tumor. For one thing, adoptive immunity therapy transfers cell toxicant active lymphocyte with anti-tumor activity to tumor host. For another, combination of TIL, LAK/IL-2 and IFN/IL-2 may lead to the development of new therapies effective to human malignant tumor.

2. Inducement and differentiation therapy: Inducement and differentiation therapy for tumor is a new area of tumor therapeutics. The therapy is different from traditional chemical therapy and radiotherapy. The difference does not lie in that it does not kill tumor cells, but that it induces the tumor cells to differentiate towards mature phase under the effect of differentiated inducement agent, recover the normal or approximately normal representation and functions of the cell. Since the active mechanism of differentiated inducement is different from radiotherapy and chemical therapy, the experimental research of differentiated inducement focuses on research on proliferation and differentiated inducement. Clinic application is divided into inducement and differentiation therapy of tumor and inducement and extinction therapy of tumor. Inducement and differentiation therapy adopts the following inducement and differentiation agents: vitamin D3, phorbol, cytokine, ATRA, inducement and extinction is As2O3. In 1986, Ruijin Hospital of Shanghai Second Medical University first applied ATRA inducement and differentiation therapy to APL, obtaining a high remission rate. In 1992, Harbin Medical University used As2O3 173 traditional Chinese medicine solution to treat APL, obtaining a very high remission rate. Later on, through further research, it was found that using ATRA and As2O3 to treat APL offered successful examples for tumor treatment by inducement and differentiation and extinction.

3. Biological therapy: One of the major achievements in life science and medical science in 1980s is the rapid emergence of a new study—biological therapy or bioregulator therapy based on the development of medical molecular biology, molecular immunity, oncology and cytokine. Modern biological therapeutics is deep and broad in research content and scope. The basic characteristics of scientifically grounded modern biological therapeutics are: the preparations used in biological therapy are self substances in the organism, its radical differences from radiotherapy and chemical therapy lie in: it has no progressive damage on normal tissues and cells of the organism, especially immune structure and function, but has regulatory and enhancing effect. As is known, radiotherapy and chemical therapy are different in this aspect. As a non-selective damage therapy, it injures normal histiocyte of the organism while damaging cancer tissue, and tend to cause serous consequences due to serious damage on marrow hematopiesis system and immune structure and function.

The research on anti-cancer biological therapy focuses on basic theories and clinic application technologies of biological therapies such as anticancer cell therapy, i.e. anticancer cell system (NK cell group, K cell group, TK cell group, LAK cell group, macrophage, etc); anticancer cytokine therapy, i.e. anticancer cytokine system (IFN, IL-2, TNF, etc); anticancer gene therapy, i.e. anticancer gene system (Rb gene, P53 gene, other genes, etc), and anticancer antibody.

4. New tumor vaccine research and development and gene therapy in recent years offers more promising prospect

More efforts will be undoubtedly made to develop more reasonable and effective comprehensive therapies for tumor treatment in the future. Biological therapy will plays a more vital role in treatment with development of the times. With the change of traditional ideas, tumor therapy will leap forward in quality.

(1) Biological response modifier will be applied more widely, so will immunological control therapy.

(2) Cell differentiation and inducement agent open a new path for tumor treatment.

(3) Gene therapy will have broad prospect.

(4) Blood vessel growth inhibitor will be applied.

(5) Comprehensive therapy will become the direction of tumor treatment.

With the rapid development of biological technology in medical field, coupled with further understanding of tumor pathogenesis on cellular element level, tumor treatment has entered a new era, shifting from the ear of cell toxicant treatment to the era of targeting treatment. The so called targeting treatment means that drugs are aimed at the intended target, without injuring other normal cells, tissues or organs. Targeting treatment is classified into three types: first, aiming at a particular organ, for example, some drug is only effective to the tumor in a particular organ, which is called organ targeting; second, cell targeting, which refers to exclusively aiming at the tumor cells of a particular type; third, molecule targeting, which means aiming at some part of a particular protein family in tumor cells, or segments of a nucleotide or a gene product for treatment.

In light of the overall strategy, tumor treatment is designed to eliminate the tumor cells below a particular order of magnitude by various methods (it is reported that this order of magnitude is 10⁶ for mice, 3.5x10⁹ for human cells, approximately equivalent to globular node with the diameter of 1.5cm), re-motivate, reactivate and recover immunological functions of human body itself under the condition, fulfilling the purpose of long-term peaceful coexistence with tumor, which is the tumor treatment in the 21st century.

CHAPTER 2

Thymic Aplasia and Inferior Immunologic Function:

One of the Possible Pathogenic Factors of Cancer

[Abstract]

Objectives: Probe into the pathogenic factors and pathophysiology of cancer.

Method: Firstly we probe into the relation between thymus removal and inferior immunologic function and the establishment of cancer-bearing animal models so as to make the experimental study on cancer-bearing animal models.

Results: The cancer-bearing animal model can be established after removal of the thymus of the mouse and it is helpful to establish the cancer-bearing animal model through injection of immunosuppressant.

Conclusions: The occurrence and development of cancer has obviously affirmative relation with the thymus of the immune organ of the host and its functions.

Keywords: thymic aplasia, immunologic function, cancer-bearing animal model

This lab has made a series of experimental study on animal to probe into the pathogenic factors and pathophysiology of cancer. Through analyzing and reflecting the results of experimental study, we obtain new findings, new thinking and new enlightenments: one of the pathogenic factors may be thymus atrophy, damaged thymus function and inferior immunologic function. Therefore, Professor Xu Ze initiated that one of the pathogenic factors may be thymus atrophy, damaged function of central immune organ, inferior immunologic function, inferior immunological surveillance and immunologic escape. However, what causes the thymus atrophy of the host? Through repeated consideration and inference, the author holds that maybe the solid tumor produces one factor to inhibit the thymus, which shall be further studied by experiment and is called cancer-based thymus-inhibiting factor temporarily by us.

I. Experimental study to probe into pathogenic factors and physiopathology of cancer

This lab has made a series of experimental study on animal to probe into the pathogenic factors and pathophysiology of cancer. Firstly, we made intravital specimen of aseptic tumor into homogenate unicell suspending liquid and tried to transplant it on the experimental animal, but we failed time and again. Subsequently, we ablated the thymus of the mouse and then we succeeded in the transplantation. Some mouse was injected with cortisone to reduce the immunity of the mouse, in this way, the transplantation was successful. The method of thymus removal: take one Kunming white rat aged 8-10 weeks, 21±2g, no matter it is female or male, incise the skin at the breast, cut off 2nd, 3rd and 4th rib, separate them slightly to expose the thymus to quickly remove it and then close the chest cavity rapidly. Then we raised the rat and made the formal experiment after 2 weeks and established the cancer-bearing animal model. Establishment of cancer-bearing animal model: take the fresh tumor from the tumor-bearing rat to make the unicell suspending liquid, after dyeing the cancer cells with lichenin and counting (1x10⁶/ml), make the hypodermic inoculation at the left side of each rat with 0.2ml physiological saline for cancer cells.

Observation index: weigh the rat every 3 days and measure the diameter of the tumor with vernier caliper, measure the immunologic function and determine the blood picture. Finally, after removal of the thymus of 30 rats, the inoculation was successful.

Through transplantation in 5th days after thymus removal, the node as large as a soybean came out after 5-6 days and the tumor as large as a finger came out after 10-21 days, the transplanted cancer could survive for 3-4 weeks, however, the passage failed.

Experimental study to probe into the pathogenic factors and physiopathology—new findings

This lab has the following findings from the experimental tumor study:

Experiment 1: this lab excises the thymus (TH) of 30 mice and establishes the cancer-bearing animal model. It is helpful to establish the cancer-bearing animal model through injecting the depressant. It is proven by the study conclusions: the occurrence and development of the cancer has remarkably affirmative relation with the thymus of the immune organ of the host and its functions.

Experiment 2: Does the inferior immune lead to the cancer or the cancer lead to the inferior immune at all? Our experimental results: the inferior immune leads to the occurrence and development of the cancer, without the descent of immunologic function, it is not easy to realize the successful inoculation. It is suggested by the experimental results: improving and maintaining the good immunologic function and protecting the good thymus of the central immune organ are the important measures for preventing the occurrence of cancer.

Experiment 3: in studying the relation between the metastasis of cancer and the immune, this lab establishes 60 animal models for liver metastatic carcinoma, which are divided into two groups including Group A applied with immune depressant and Group B not applied with immune depressant. Results: the metastatic lesions in the liver in Group A are obviously more than the ones in Group B. It is suggested by the experimental results: metastasis is related to the immune and inferior immunologic function or application of immune depressant may promote the tumor metastasis.

Experiment 4: When making experiments to probe into the effects of tumor on immune organ, this lab finds that the thymus meets with progressive atrophy with the advance of the cancer (600 cancer-bearing animal model mice). The thymus of the host meets with the acute progressive atrophy after the cancer cells are inoculated, the cell proliferation is prevented and the volume is obviously shrunk. It is suggested by the experimental results: the tumor may inhibit the thymus, resulting in the atrophy of the immune organ.

Experiment 5: we also find through experiment that if some experimental mice are not successfully inoculated or the tumor is very small, the thymus is not obviously shrunk. In order to understand the relation between the tumor and the atrophy of the thymus, we excise the transplanted solid tumor of one group of mice when it grows up to the size of a thumb. After one month, through anatomy, we find the thymus does not meet with progressive atrophy again. Therefore, it is inferred by us that maybe the solid tumor produces one kind of unknown factor to inhibit the thymus, which shall be further studied through experiment.

Experiment 6: it is proven by the above-mentioned experimental results: the advance of the tumor makes the thymus meet with progressive atrophy, then, can we take some measures to prevent the atrophy of the thymus of the host? Therefore, we further perfect the design to seek for the method or drug to prevent the atrophy of the thymus of the cancer-bearing mice through the experimental study on animal. So we make the experimental study to recover the function of the immune organ through cell transplantation of the immune organ. We discuss the atrophy of the thymus of the immune organ in preventing the advance of tumor, seek for the method to recover the functions of the thymus and reconstruct the immune, carry out the cell transplantation of foetal liver, spleen and thymus with the mice and establish the immunologic function through adoptive immunity. It is shown by the results: through the joint transplantation of three groups of cells, namely S, T and L (200 experimental mice), the entire extinction rate of the tumor in the long term is 46.67% and the one with the entire extinction of the tumor get a long survival life.

Experiment 7: in the experiment to probe into the effects of tumor on the immune organ such as spleen, we find: the spleen can inhibit the growth of the tumor in the early stage of the tumor, however, in the late stage, the spleen meets with the progressive atrophy. It is suggested by the study results: the effects of spleen on the growth of the tumor are embodied into bi-direction, in the early stage, it can inhibit the tumor to a certain extent, however, in the late stage, it fails to inhibit the tumor. The cell transplantation of the spleen can enhance the role of inhibiting the tumor.

Experiment 8: it is suggested by the results of the follow-up survey: control over the metastasis is the key to cancer treatment. Now it is well known that the cancer cell metastasis has multiple steps and links. In order to try to interrupt one link so as to prevent the metastasis, we consider the formation of the regenerative blood vessel of tumor is one of the links in which the metastatic cancer cells can nidate, root and grow into the cancer node or not. In 1986, this lab was making the microcirculation study and we observed the formation of the blood capillary of transplanted tumor node of cancer-bearing mice and its flow rate and flow with the micro-circle microscope; then we tried to seek for the drugs for prevention of the formation of the tumor blood vessel from the natural herbs, observed the formation process of the regenerative blood vessel with Olympus micro-circle microscope photograph system and counted the flow rate and flow of the arteriole and venule, found Common Threewingnut Root acetic ether extract (TG) from the traditional Chinese herbs and carried out the blood vessel inhibition test. It was found from the results: in the first day of inoculation there was no regenerative blood vessel and in the second day it was found that the fine micro regenerative blood vessel grew up. TG can reduce the density of the regenerative blood capillary of the tumor.

Experiment 9: we also found from a large batch of tumor-bearing animal models in the lab that the more the hypodermically inoculated solid tumor of some cancer-bearing experimental mice, the more different the cancer cells of the central tissue of the transplanted solid tumor from the peripheral cancer cells. The center of the node is mostly aseptically necrosed or liquefied its periphery is still surrounded with active cancer cells. Therefore, in the clinical treatment, we adopted the measures to treat the aseptic necroses.

II. Probing into the method of progressive atrophy of thymus of central immune organ and reconstructing the immune in preventing the advance of tumor

From the above-mentioned experimental study, it is analyzed and held